1. Field of the Invention
This invention relates to a method of lowering intraocular pressure and treating glaucoma in mammals using corynanthine and compounds related to corynanthine and particularly to the topical application of these compounds to the eye of mammals in order to lower the intraocular pressure caused by glaucoma.
Glaucoma refers to a group of diseases of the eye which are characterized by abnormally high intraocular pressure. The outer shell of the eyeball is made up of three coats. A tough outer fibrous tunic composed of variously arranged connective tissue fibers, the uveal tunic and the retina. The choroid is the posterior segment of the uveal tunic. The anterior part of the uvea, in part, is referred to as the ciliary body and is lined with two epithelial cell layers which secrete the aqueous humor which fills the anterior chamber of the eye. In a healthy eye the humor flows from the ciliary body through the pupil into the anterior chamber of the eye and leaves the eye through Schlemm's canal. The rate of formation and the rate of exit of this aqueous humor determines the intraocular pressure in the eyeball.
In subjects suffering from glaucoma the rate of elimination of aqueous humor from the eye is reduced which results in fluid build up within the eye and increased intraocular pressure. If high intraocular pressure is allowed to continue untreated it interferes with the blood supply to the nerve fibers of the retina and optic nerve and if left uncorrected the optic nerve dies and blindness results.
Glaucoma can be treated both through surgery or therapeutically with drugs. Surgery seeks to create new outlets for the aqueous humor and thereby reduce the intraocular pressure. A number of drugs have been discovered which when either taken internally or applied topically to the eye lower intraocular pressure but many are toxic and cause undesirable side effects, especially when used as chronic therapy.
2. Description of the Prior Art
Adrenergic agents have been explored for the treatment of chronic open-angle glaucoma. Epinephrine, a nonspecific .alpha. and .beta. adreneric agonist, and Timoptic, a .beta. adrenergic antagonist are currently used clinically for the treatment of glaucoma. Other drugs with predominantly .alpha. adrenergic antagonist receptor specificity, such as prazosin and thymoxamine, have been examined with respect to their effect on intraocular pressure. Prazosin and thymoxamine successfully reduce intraocular pressure in rabbits. Neither drug however has been effective in reducing intraocular pressure in humans.
The present treatment of open-angle glaucoma is limited to four types of pharmacologic agents: (1) the topically applied cholinergic agents, pilocarpine, carbachol, and phospholine iodide, (2) the topically applied but nonselective .alpha. and .beta. adrenergic agonist, epinephrine, (3) the topically applied .beta. adrenergic antagonist, timolol, and (4) the systemically administered carbonic anhydrase inhibitors acetazolamide and methazolamide. There is currently a need for more effective and selective adrenergic agents for the treatment of glaucoma to eliminate undesirable side effects of the presently employed drugs, and to widen the range of therapeutic choices.
The effects of .alpha. adrenergic agents on aqueous humor dynamics have been studied in several different species. Some of the drugs that have been investigated have different effects on ocular aqueous humor parameters in different species. Varying responses to the same drug have been found which is perhaps due to differences in adrenergic receptor quantity, location and regulation amongst the species.
Innemee et al. in a paper entitled Differential Effects of Selective .alpha..sub.1 and .alpha..sub.2 Adrenoceptor Agonists on Intraocular Pressure in the Conscious Rabbit. Doc Ophthalmol 52:287, 1982 recently studied the effects of selective .alpha..sub.1 and .alpha..sub.2 adrenergic agonists on intraocular pressure in rabbits. They demonstrated that the topical application of the selective .alpha..sub.1 agonists, phenylephrine and St 587, caused an initial elevation in intraocular pressure, followed by a fall in pressure below baseline values. Topical application of the selective .alpha..sub.2 agonist B-HT 920 resulted in a prolonged ocular hypotensive effect. However, Lee and Brubaker in "Effect of Phenylephrine on Aqueous Humor Flow", Curr Eye Res 2:89, 1982 demonstrated that phenylephrine had no effect on intraocular pressure or aqueous humor secretion in man.
Clonidine is a nonselective .alpha..sub.1 and .alpha..sub.2 adrenergic agonist. It is known to reduce intraocular pressure in humans and monkeys, but raises intraocular pressure in rabbits. It has no effect on outflow facility or aqueous humor flow rates in monkeys, and no effect on outflow facility in humans, Hodapp E, et al.: The Effect of Topical Clonidine on Intraocular Pressure, Arch Ophthalmol 99:1208, 1981; Bill A, Heilmann K: Ocular Effects on Clonidine in Cats and Monkeys (macaca irus), Exp Eye Res 21:481, 1975; Krieglstein GK, et al.: The Peripheral and Central Neural Actions of Clonidine in Normal and Glaucomatous Eyes, Invest Ophthalmol Vis Sci 17:149, 1978. Norepinephrine, a nonselective .alpha. agonist, lowers intraocular pressure in rabbits, by increasing outflow facility and reducing aqueous humor flow, Green K, Padgett D: Effect of Various Drugs on Pseudofacility and Aqueous Humor Formation in the Rabbit Eye, Exp Eye Res 28:239, 1979. It has no effect on intraocular pressure, outflow facility or aqueous humor flow rates in monkeys, Bill A: Effects of Norepinephrine, Isoproterenol and Sympathetic Stimulation on Aqoueous Humor Dynamics in Vervet Monkeys, Exp Eye Res 10:31, 1970. Epinephrine, a nonselective .alpha. and .beta. agonist, reduces intraocular pressure in rabbits and humans, Langham ME, Krieglstein GK: The Biphasic Intraocular Pressure Response of Rabbits to Epinephrine, Invest Ophthalmol Vis Sci 15:119, 1976; Townsend DJ, Brubaker RF: Immediate Effect of Epinephrine on Aqueous Formation in the Normal Human Eye as Measured by Fluorophotometry, Invest Ophthalmol Vis Sci 19:256, 1980. It causes an initial increase in intraocular pressure in monkeys, Bill A: Early Effects on Epinephrine on Aqueous Humor Dynamics in Vervet Monkeys (cercopithecus ethiops), Exp Eye Res 8:35, 1969. It increases outflow facility in all three species, reduces aqueous humor flow rates in rabbits, increases aqueous flow in humans and has no effect on aqueous humor flow in monkeys, Lorenzetti OJ: Dose-Dependent Influence of Topically Instilled Adrenergic Agents on Intraocular Pressure and Outflow Facility in the Rabbit, Exp Eye Res 12:80, 1971; Barany EH: Topical Epinephrine Effects on True Outflow Resistance and Pseudofacility in Vervet Monkeys Studied by a New Anterior Chamber Perfusion Technique, Invest Ophthalmol Vis Sci 7:88, 1968.
Thymoxamine, a relatively nonselective .alpha. adrenergic antagonist has no effect on intraocular pressure, outflow facility or aqueous humor flow rates in humans but reduced intraocular pressure in rabbits, Lee DA, et al.: Effect of Thymoxamine on Aqueous Humor Formation in the Normal Human Eye as Measured by Fluorophotometry, Invest Ophthalmol Vis Sci 21:805, 1981; Sobel LI, et al.: Adrenergic Receptors in Rabbit Iris-ciliary Body Quantitation of the Alpha-2 Subtype, Invest Ophthalmol Vis Sci, Suppl 24:89, 1983. Nylidrin, a selective .alpha..sub.1 antagonist and nonselective .beta. agonist, lowers intraocular pressure in all three species, Sobel L, et al.: Topical Nylidrin and Aqueous Humor Dynamics in Rabbits and Monkeys, Arch Ophthalmol (in press); Bucci MG: Effects of New Topical .beta.-mimetic (isoxuprine and nylidrin) and .beta.-lytic (oxprenolol) Agents on the Ocular Pressure in Glaucomatous eyes, Ophthalmol Res 9:238, 1977. It has no effect on outflow facility or aqueous humor flow rates in monkeys and rabbits. Prazosin, a selective .alpha..sub.1 antagonist, reduces intraocular pressure in rabbits, without changing outflow facility, Rowland JM, Potter DE: The Effects of Topical Prazosin on Normal and Elevated Intraocular Pressure and Blood Pressure in Rabbits, Eur J Pharmacol 64:361, 1980; Krupin T, et al.: Effect of Prazosin on Aqueous Humor Dynamics in Rabbits, Arch Ophthalmol 98:1639, 1980. Posterior chamber ascorbate measurements indicate prazosin also reduces aqueous flow rates in rabbits.